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Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor

死亡受体联合靶向治疗胰腺癌

基本信息

批准号：
7962128
负责人：
DONALD J. BUCHSBAUM
金额：
$ 18.36万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7962128
关键词：
Accounting Adaptor Signaling Protein Address Advanced Malignant Neoplasm Adverse effects Agonist American Society of Clinical Oncology Animal Model Antibodies Apoptosis Apoptosis Inhibitor Attention Biological Markers Biology Cancer Center Cancer Model Cancer Patient Cancer cell line Caspase Cell Death Cell Line Cell surface Cessation of life Clinical Clinical Trials Combined Modality Therapy Complex Credentialing Data Death Domain Development Disease Disseminated Malignant Neoplasm Doctor of Medicine Dose Enrollment Epidermal Growth Factor Receptor Evaluation Exhibits External Beam Radiation Therapy Family Funding Future Goals Grant Hepatocyte Human Human Genome In Vitro Induction of Apoptosis Instruction Lead Licensing Ligands Literature Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Mediating Membrane Minnesota Modality Modeling Molecular Molecular Profiling Monoclonal Antibodies Monoclonal Antibody C225 Monoclonal Antibody Therapy Mus Newly Diagnosed Normal Cell Pancreas Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Play Predisposition Primates Production Progress Reports Property Proteomics Protocols documentation Public Health Quality Control RNA Helicase Radiation Radiation therapy Radiation-Sensitizing Agents Reagent Recruitment Activity Regimen Regulation Reporting Reproduction spores Research Resistance Role Science Signal Transduction Site Staging TNFRSF10A gene TNFSF10 gene Tail Technology Testing Therapeutic Therapeutic Agents Tissue Sample Tissues Toxic effect Toxicology Translating Translational Research Translations Treatment Efficacy Treatment Protocols Tumor Cell Line Universities University of Alabama at Birmingham Cancer Center University of Minnesota Cancer Center Xenograft Model Xenograft procedure abstracting assay development base cancer cell cancer therapy chemotherapeutic agent chemotherapy clinical efficacy cytotoxicity docetaxel drug development gemcitabine in vivo industry partner inhibitor/antagonist irinotecan malignant breast neoplasm neoplastic cell novel novel therapeutics oxaliplatin pancreas xenograft pancreatic neoplasm patient population pre-clinical preclinical study programs protein complex receptor response small molecule synergism therapeutic target treatment strategy trend tumor tumor immunology

项目摘要

PROJECT SUMMARY (See instructions); This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.

项目总结(见说明)；这项建议是原孢子赠款中项目2的延续。与这项提议相关的是，我们有通过体外研究开发了一种抗DRS单抗治疗胰腺癌的方法。与行业合作伙伴(Daiichi Sankyo)合作的第一阶段和最近完成的第二阶段试验胰腺癌。我们还发现了一种新的分子(DDX3)，它似乎扮演着重要的角色在调节抗DRS介导的细胞凋亡方面。在这项建议中，我们将探讨两个策略，以加强抗DRS单抗治疗胰腺癌的疗效观察对抗DRS有抵抗力。这两种策略是评估添加抗DR4的单抗试剂或小分子调节剂的加入导致了细胞凋亡的级联。这两种细胞凋亡调节剂是被评估的是一种Bcl2家族的抑制剂AT-101和一种LAP家族的抑制剂AT-406。这两个战略将使用体外分析和原位和转移性胰腺癌模型进行研究导致了最佳策略的第一阶段试验。此外，我们还将继续研究DDX3和 DRS/DDX3复合体作为肿瘤细胞对死亡受体介导的敏感性/耐药性的生物标志物抗肿瘤效应，并作为抗DR介导的抗肿瘤效应增强策略的靶点。